Hydantoin derivatives as therapeutic agents

ABSTRACT

A series of spiro-hydantoin compounds has been prepared by condensing the appropriate carbonyl ring compound, such as the corresponding 1-indanone, 1-tetralone, 4-chromanone, thiochroman-4-one, 7,8-dihydroquinolin-5(6H)-one, 6,7-dihydropyrindin-5(5H)-one, thiondane-3-one-1,1-dioxide and 4-oxoisothiochroman-2,2-dioxide, respectively, with potassium cyanide and ammonium carbonate. The resulting hydantoin derivatives are found to be useful in preventing or alleviating chronic diabetic complications. Preferred member compounds include spiro-[imidazolidine-4,1&#39;-indan]-2,5-dione, 6-fluoro-spiro-[chroman-4,4&#39;-imidazolidine]-2&#39;,5&#39;-dione, 6-chloro-spiro-[chroman-4,4&#39;-imidazolidine]-2&#39;,5&#39;-dione, 6,7-dichloro-spiro-[chroman-4,4&#39;-imidazolidine]-2&#39;,5&#39;-dione, 6,8-dichloro-spiro-[chroman-4,4&#39;-imidazolidine]-2&#39;,5&#39;-dione, 6&#39;-fluoro-spiro-[imidazolidine-4,4&#39;-thiochroman]-2,5-dione and 6&#39;,7&#39;-dichloro-spiro-[imidazolidine-4,4&#39;-thiochroman]-2,5-dione.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 767,803 filedFeb. 11, 1977, now U.S. Pat. No. 4,117,230 which is acontinuation-in-part of application Ser. No. 733,062, filed Oct. 18,1976 now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to new and useful hydantoin derivatives in thefield of medicinal chemistry. More particularly, it is concerned with anovel series of spiro-hydantoin compounds, which are of especial valuein view of their ability to control certain chronic complicationsarising from diabetes mellitus (e.g., diabetic cataracts andneuropathy). The invention also includes a new method of therapy withinits scope.

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and betteroral antidiabetic agents. For the most part, these efforts have involvedthe synthesis and testing of various heretofore new and unavailableorganic compounds, particularly in the area of the sulfonylureas, in anendeavor to determine their ability to lower blood sugar (i.e., glucose)levels to a substantially high degree when given by the oral route ofadministration. However, in the search for newer and still moreeffective antidiabetic agents, little is known about the effect of otherorganic compounds in preventing or arresting certain chroniccomplications of diabetes, such as diabetic cataracts, neuropathy andretinopathy, etc. Nevertheless, K. Sestanj et al. in U.S. Pat. No.3,281,383 do disclose that certain aldose reductase inhibitors like1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and someclosely-related derivatives thereof are useful for these purposes, eventhose these particular compounds are not known to be hypoglycemic innature. These particular aldose reductase inhibitors all function byinhibiting the activity of the enzyme aldose reductase, which isprimarily responsible for regulating the reduction of aldoses (likeglucose and galactose) to the corresponding polyols (such as sorbitoland galactitol) in the human body. In this way, unwanted accumulationsof galactitol in the lens of galactosemic subjects and of sorbitol inthe lens, peripheral nervous cord and kidney of various diabeticsubjects are thereby prevented or otherwise reduced as the case may be.As a result, these compounds, are definitely of value as aldosereductase inhibitors for controlling certain chronic diabeticcomplications, including those of an ocular nature, since it is alreadyknown in the art that the presence of polyols in the lens of the eyeinvariably leads to cataract formation together with a concomitant lossof lens clarity.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been rathersurprisingly found that various spiro-hydantoin compounds are extremelyuseful when employed in therapy as aldose reductase inhibitors for thecontrol of certain chronic diabetic complications in a host subject towhom they are administered. More particularly, the novel method oftreatment of the present invention involves treating a diabetic host toprevent or alleviate diabetes-associated chronic ocular complications byadministering to said host an effective amount of a compound of theformulae: ##STR1## and the base salts thereof with pharmacologicallyacceptable cations, wherein W is--(CH₂)_(n) --; X is hydrogen and X¹ ishydrogen, hydroxy, fluorine, chlorine, lower alkyl or lower alkoxy (eachhaving from one to four carbon atoms); or X and X¹, when takenseparately, are each chlorine, lower alkyl or lower alkoxy and whentaken together are --OCH₂ (CH₂)_(n) O--; Y is oxygen or sulfur; Z is W,Y or Q wherein Q is ##STR2## and n is zero or one. These compounds areall potent aldose reductase inhibitors and therefore possess the abilityto markedly reduce or even inhibit sorbitol accumulation in the lens andperipheral nerves of various diabetic subjects.

More specifically, the novel compounds of this invention are those offormula I that are disubstituted (X and X¹ are each other than hydrogen)and those of formula I that are monosubstituted (X is hydrogen) where Zis (CH₂)_(n) and n is zero and X¹ is other than hydrogen, 4-chlorine and5-butyl; Z is (CH₂)_(n) and n is one and X¹ is other than hydrogen,5-methoxy, 6-methoxy or 5-butoxy; Z is oxygen and X¹ is other thanhydrogen, 6-chlorine, 6-bromine, 8-chlorine, 6-methyl and 6-ethyl, and Zis sulfur and X¹ is other than hydrogen. Additionally, those compoundsof formula I where Z is Q, as well as those compounds of formulae II-IIIare also all novel compounds.

Accordingly, the novel compounds of formula I comprise spiro-hydantoincompounds of the formula: ##STR3## and the base salts thereof withpharmacologically acceptable cations, wherein X is hydrogen and X² isfluorine, hydroxy or 6'-(lower alkoxy); or X and X², when takenseparately, are each lower alkoxy, and when taken together are --OCH₂(CH₂)_(n) O--; and n is zero or one.

The novel compounds of formula I also comprise spirohydantoins of theformula: ##STR4## and the base salts thereof with pharmacologicallyacceptable cations, wherein X is hydrogen and X³ is fluorine, chlorineor bromine; or X and X³, when taken separately, are each chlorine andwhen taken together are --OCH₂ (CH₂)_(n) O--; and n is zero or one.

The novel compounds of formula I additionally comprise spiro-hydantoinsof the formula: ##STR5## and the base salts thereof withpharmacologically acceptable cations, wherein X is hydrogen and X⁴ isfluorine, hydroxy or lower alkoxy; or X and X⁴, when taken separately,are each chlorine or lower alkoxy, and when taken together are --OCH₂(CH₂)_(n) O--; Y is oxygen or sulfur; and n is zero or one.

Lastly, the novel compounds of formula I also comprise spiro-hydantoincompounds of the formula: ##STR6## and the base salts thereof withpharmacologically acceptable cations, wherein X is hydrogen and X⁵ isfluorine, chlorine, bromine or lower alkoxy; or X and X⁵, when takenseparately, are each chlorine or lower alkoxy, and when taken togetherare --OCH₂ (CH₂)_(n) O--; Q is ##STR7## and n is zero or one.

Of especial interest in this connection are such typical and preferredmember compounds of the invention asspiro-[imidazolidine-4,1'-indan]-2,5-dione,6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione,6-chloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione,6,7-dichloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione6,8-dichloro-spiro-[chroman-4,4'-thiochroman]-2',5'-dione and6',7'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione,respectively. These particular compounds are all highly potent asregards their aldose reductase inhibitory activity, in addition to beingextremely effective in lowering sorbitol levels in the sciatic nerve andlens of diabetic subjects and galactitol levels in the lens ofgalactosemic subjects to a remarkably high degree. The preferred6-fluoro and 6,8-dichloro derivatives are, as previously indicated, newcompounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for preparing the compounds ofthis invention, an appropriate carbonyl ring compound, such as thecorresponding 1-indanone, 1-tetralone, 4-chromanone, thiochroman-4-one,7,8-dihydroquinolin-5(6H)-one, 6,7-dihydropyrindin-5(5H)-one,thioindane-3-one-1,1-dioxide and 4-oxoisothiochroman-2,2-dioxide of therespective formulae: ##STR8## wherein W, X, X¹, Y and Z are allpreviously defined, is condensed with an alkali metal cyanide (e.g.,sodium cyanide or potassium cyanide) and ammonium carbonate to form thedesired spiro-hydantoin final product of the structural formulaepreviously indicated. This particular reaction is normally carried outin the presence of a reaction-inert polar organic solvent medium inwhich both the reactants and reagents are mutually miscible. Preferredorganic solvents for use in this connection include cyclic ethers suchas dioxane and tetrahydrofuran, lower alkylene glycols like ethyleneglycol and trimethylene glycol, water-miscible lower alkanols such asmethanol, ethanol and isopropanol, as well as N,N-di(lower alkyl) loweralkanoamides like N,N-dimethylformamide, N,N-dimethylformamide andN,N-dimethylacetamide, etc. In general, the reaction is conducted at atemperature that is in the range of from about 20° C. up to about 120°C. for a period of about two hours to about four days. Although theamount of reactant and reagents employed in the reaction can vary tosome extent, it is preferable to employ at least a slight molar excessof the alkali metal cyanide reagent with respect to the carbonyl ringcompound starting material in order to effect maximum yield. Uponcompletion of the reaction, the desired product is easily isolated in aconventional manner, e.g. by first diluting the reaction mixture withwater (boiling if necessary) and then cooling the resultant aqueoussolution to room temperature, followed by acidification to afford theparticular spiro-hydantoin compound in the form of a readily-recoverableprecipitate.

Needless to say, compounds of the invention in which Z of formula I is Qand Q is ##STR9## can be prepared from those compounds wherein Z issulfur by merely oxidizing the latter group of compounds in accordancewith standard techniques well known to those skilled in the art. Forinstance, the use of sodium periodate in this connection leads to theformation of the oxosulfur compounds, while peroxy acids like peraceticacid, perbenzoic acid and m-chloroperoxybenzoic acid, etc., arepreferably employed to afford the corresponding dioxosulfur compounds.On the other hand, certain compounds of the invention having a ringsubstituent (X, X¹, etc.) which is halogen (as previously defined) mayalternatively be prepared from the corresponding unsubstituted compoundswherein at least one of X and X¹ is hydrogen by means of directhalogenation techniques well known to those in the field of syntheticorganic chemistry.

The starting materials required for preparing the spirohydantoincompounds of this invention are, for the most part, known compounds areeither readily available commercially, like 1-indanone and6-chloro-4-chromanone, etc., or else they can easily be synthesized bythose skilled in the art starting from common chemical reagents andusing conventional methods of organic synthesis. For instance,6-fluoro-4-chromanone is obtained by condensingβ-(p-fluorophenoxy)propionic acid in the presence of polyphosphoricacid, while 6,7-dichlorothiochroman-4-one is obtained by condensingβ-(3,4-dichlorophenylthio)-propionic acid in the presence ofconcentrated sulfuric acid. In both cases, the starting organic acid isultimately derived from a commercially available compound.

The chemical bases which are as reagents in this invention to preparethe aforementioned pharmaceutically acceptable base salts are thosewhich form non-toxic salts with the various herein described acidicspiro-hydantoin compounds, such as6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, for example.These particular non-toxic base salts are of such a nature that theircations are said to be essentially non-toxic in character over the widerange of dosage administered. Examples of such cations include those ofsodium, potassium, calcium and magnesium, etc. These salts can easily beprepared by simply treating the aforementioned spiro-hydantoin compoundswith an aqueous solution of the desired pharmacologically acceptablecation, and then evaporating the resulting solution to dryness whilepreferably being placed under reduced pressure. Alternatively, they mayalso be prepared by mixing lower alkanoli solutions of the said acidiccompounds and the desired alkali metal alkoxide together, and thenevaporating the resulting solution to dryness in the same manner asbefore. In either case, stoichiometric quantities of reagents must beemployed in order to ensure completeness of reaction and maximumproduction of yields with respect to the desired final product.

As previously indicated, the spiro-hydantoin compounds of this inventionare all readily adapted to therapeutic use as aldose reductaseinhibitors for the control of chronic diabetic complications, in view oftheir ability to reduce lens sorbitol levels in diabetic subjects to astatistically significant degree. For instance,6-fluoro-spiro-[chroman-4,4'-imidazolidine]2',5'-dione, a typical andpreferred agent of the present invention, has been found to consistentlycontrol (i.e., inhibit) the formation of sorbitol levels in diabeticrats to a significantly high degree when given by the oral route ofadministration at dose levels ranging from 0.75 mg./kg. to 20 mg./kg.,respectively, without showing any substantial signs of toxic sideeffects. The other compounds of this invention also cause similarresults. Furthermore, all the herein described compounds of thisinvention can be administered by either the oral or parenteral routes ofadministration, for the present purposes at hand, without causing anysignificant untoward pharmacological side reactions to occur in thesubject to whom they are so administered. In general, these compoundsare ordinarily administered in dosages ranging from about 0.1 mg. toabout 10 mg. per kg. of body weight per day, although variations willnecessarily occur depending upon the weight and condition of the subjectbeing treated and the particular route of administration chosen.

In connection with the use of the spiro-hydantoin compounds of thisinvention for the treatment of diabetic subjects, it is to be noted thatthese compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by either of the routes previouslyindicated, and that such administration can be carried out in bothsingle and multiple dosages. More particularly, the compounds of thisinvention can be administered in a wide variety of different dosageforms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents, etc. Moreover, such oralpharmaceutical formulations can be suitably sweetened and/or flavored bymeans of various agents of the type commonly employed for just suchpurposes. In general, the therapeutically useful compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 0.5% to about 90% by weight of the total composition,i.e., in amounts which are sufficient to provide the desired unitdosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When cusous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes, and if so desired, emulsifying and/or suspending agentsas well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particularspiro-hydantoins in sesame or peanut oil or in aqueous propylene glycolmay be employed, as well as sterile aqueous solutions of thecorresponding water-soluble, alkali metal or alkaline-earth metal saltspreviously enumerated. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal injection purposes. In this connection, the sterileaqueous media employed are all readily obtainable by standard techniqueswell-known to those skilled in the art. Additionally, it is alsopossible to administer the aforesaid spiro-hydantoin compounds topicallyvia an appropriate opthalmic solution suitable for the present purposesat hand, which can then be given dropwise to the eye.

The activity of the compounds of the present invention, as agents forthe control of chronic diabetic complications, is determined by theirability to successfully pass one or more of the following standardbiological and/or pharmacological tests, viz., (1) measuring theirability to inhibit the enzyme activity of isolated aldose reductase; (2)measuring their ability to reduce or inhibit sorbitol accumulation inthe sciatic nerve of acutely streptozotocinized (i.e., diabetic) rats;(3) measuring their ability to reverse already-elevated sorbitol levelsin the sciatic nerve and lens of chronic streptozotocin-induced diabeticrats; (4) measuring their ability to prevent or inhibit galactitolformation in the lens of acutely galactosemic rats, and (5) measuringtheir ability to delay cataract formation and reduce the severity oflens opacities in chronic galactosemic rats.

Preparation A

A mixture consisting of 3.5 g. (0.019 mole) ofβ-(p-fluorophenoxy)propionic acid [Finger et al.; Journal of theAmerican Chemical Society, Vol. 81, p. 94 (1959)] and 40 g. ofpolyphosphoric acid was heated on a steam bath for a period of tenminutes and then poured into 300 ml. of ice-water. The resulting aqueousmixture was next extracted with three separate portions of ethylacetate, and the combined organic layers were subsequently washed withdilute aqueous sodium bicarbonate solution and then with water, followedby drying over anhydrous magnesium sulfate. After removal of the dryingagent by means of filtration and the solvent by means of evaporationunder reduced pressure, there was ultimately obtained a residue that wassubsequently recrystallized from ethanol to afford 2.93 g. (93%) of pure6-fluoro-4-chromanone, m.p. 114°-116° C.

Anal. Calcd. for C₉ H₇ FO₂.0.25 H₂ O: C, 63.34; H, 4.43. Found: C,63.24; H, 4.15.

Preparation B

To a solution of 12.5 g. (0.07 mole) of 3,4-dichlorobenzenethiol(available from the Aldrich Chemical Company, Inc., Milwaukee,Wisconsin) in 35 ml. of 2N aqueous sodium hydroxide and 5 ml. ofethanol, there was added an ice-cold solution consisting of 7.6 g. (0.07mole) of β-chloropropionic acid (also available from Aldrich) and 8.6 g.(0.07 mole) of sodium carbonate monohydrate dissolved in 50 ml. ofwater. The resulting reaction mixture was then heated on a steam bathfor a period of two hours, cooled to room temperature (˜25° C.) andextracted with ethyl acetate to remove any impurities. The saved aqueousportion was then poured into 300 ml. of ice-cold 3N hydrochloric acidand the precipitated solids so obtained were subsequently collected bymeans of suction filtration . After washing the latter material withwater, air-drying to constant weight and recrystallizing from ethylacetate/n-hexane, there was obtained an 11.4 g. (65%) yield ofβ-(3,4-dichlorophenylthio)-propionic acid, m.p. 70°-72° C.

Anal. Calcd. for C₉ H₈ Cl₂ S: C, 43.04; H, 3.21. Found: C, 43.13; H,3.25.

A solution of the above product in concentrated sulfuric acid wasprepared by adding 5.0 g. (0.02 mole) ofβ-(3,4-dichlorophenylthio)propionic acid to 50 ml. of ice-coldconcentrated sulfuric acid, with constant agitation being maintainedthroughout the addition step. The resulting solution was then stirred at0° C. for a period of 20 minutes and finally at room temperature foranother 20 minutes. At this point, the entire reaction mixture waspoured into 300 ml. of an ice-water mixture and the precipitated solidswere collected by suction filtration, washed with water and air-dried toconstant weight. Recrystallization from ethanol then gave 2.5 g. (54%)of pure 6,7-dichlorothiochroman-4-one, m.p. 134°-136° C.

Anal. Calcd. for C₉ H₆ Cl₂ OS: C, 46.37; H, 2.60. Found: C, 46.34; H,2.45.

Preparation C

3',4'-Dihydro-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione wasprepared according to the procedure described in Chemical Abstracts,Vol. 35, p. 6576⁷ (1941), starting from 1-indanone and other readilyavailable materials. The product obtained was identical in every respectwith the prior art compound.

EXAMPLE I

A mixture consisting of 13.2 g. (0.1 mole) of 1-indanone (available fromthe Aldrich Chemical Company, Inc., Milwaukee, Wisconsin), 9.75 g. (0.15mole) of potassium cyanide and 28.8 g. (0.3 mole) of powdered ammoniumcarbonate in 200 ml. of 50% aqueous ethanol was heated in an oil bath at75° C. for a period of 24 hours. The reaction mixture was then dilutedwith 800 ml. of water, boiled for 15 minutes and after finally beingcooled to room temperature, poured into 600 ml. of ice-cooled,concentrated hydrochloric acid. The resulting crystalline crop, whichformed as a precipitate, was subsequently collected by means of suctionfiltration, washed with water and thereafter recrystallized frommethanol-diethyl ether to afford 15.4 g. (76%) of purespiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p. 238°-240° C.[literature m.p. 239°-240° C., according to Goodson et al., Journal ofOrganic Chemistry, Vol. 25, p. 1920 (1960)].

Anal. Calcd. for C₁₁ H₁₀ N₂ O₂ : C, 65.33; H, 4.98; N, 13.86. Found: C,65.28; H, 5.01; N, 13.90.

EXAMPLE II

A mixture consisting of 2.5 g. (0.15 mole) of 6-methoxy-1-indanone(available from the Aldrich Chemical Company, Inc., Milwaukee,Wisconsin), 1.5 g. (0.23 mole) of potassium cyanide and 6.7 g. (0.07mole) of ammonium carbonate in 20 ml. of ethanol was placed in astainless-steel bomb and heated at 110° C. for a period of 20 hours.After cooling to room temperature (˜25° C.), the contents of the bombwere diluted with 100 ml. of water and then acidified to pH 2.0 with 6Nhydrochloric acid. The precipitated product so obtained was subsequentlycollected by means of suction filtration and thereafter recrystallizedfrom ethanol to give 0.49 g. (14%) of pure6'-methoxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p. 192°-194° C.

Anal. Calcd. for C₁₂ H₁₂ N₂ O₃ : C, 62.06; H, 5.21; N, 12.06. Found: C,61.94; H, 5.26; N, 12.01.

EXAMPLE III

The procedure described in Example II was repeated except that6-fluoro-1-indanone [Chemical Abstracts, Vol. 55, p. 25873a (1961)] wasthe starting material employed in place of 6-methoxy-1-indanone, usingthe same molar proportions as before. In this particular case, thecorresponding final product obtained was6'-fluoro-spiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p. 255°-257° C.The yield of pure product was 4.6% of the theoretical value.

Anal. Calcd. for C₁₁ H₁₉ FN₂ O₂ : C 60.00; H, 4.12; N, 12.72. Found: C,59.86; H, 4.33; N, 12.49.

EXAMPLE IV

The procedure described in Example II was repeated except that5,6-dimethoxy-1-indanone [Koo, Journal of the American Chemical Society,Vol. 75, p. 1891 (1953)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was5',6'-dimethoxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p.246°-248° C. The yield of pure product was 48% of the theoretical value.

Anal. Calcd. for C₁₃ H₁₄ N₂ O₄ : C, 59.53; H, 5.38; N, 10.68. Found: C,59.26; H, 5.49; N, 10.54.

EXAMPLE V

The procedure described in Example II was repeated except that5,6-methylenedioxy-1-indanone [Perkin and Robinson, Journal of theChemical Society, Vol. 91, p. 1084 (1907)] was the starting materialemployed in place of 6-methoxy-1-indanone, using the same molarproportions as before. In this particular case, the corresponding finalproduct obtained was5',6'-methylenedioxyspiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p.248°-250° C. The yield of pure product was 29% of the theoretical value.

Anal. Calcd. for C₁₂ H₁₀ N₂ O₄ : C, 58.53; H, 4.09; N, 11.38. Found: C,58.44; H, 4.14; N, 11.25.

EXAMPLE VI

The procedure described in Example II was repeated except that5-methoxy-1-indanone (available from the Aldrich Chemical Company, Inc.,Milwaukee, Wisconsin) was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was5'-methoxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p. 167°-169° C.The yield of pure product was 19% of the theoretical value.

Anal. Calcd. for C₁₂ H₁₂ N₂ O₃ : C, 62.06; H, 5.21; N, 12.06. Found: C,61.77; H, 5.23; N, 12.14.

EXAMPLE VII

The procedure described in Example II was repeated except thatthiochroman-4-one (available from Pfaltz & Bauer, Inc. of Stamford,Connecticut) was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained wasspiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p. 225°-227° C.(literature m.p. 222°-227° C., according to West German AuslegeschriftNo. 1,135,915). The yield of pure product was 44% of the theoreticalvalue.

EXAMPLE VIII

The procedure described in Example II was repeated except that6-methoxythiochroman-4-one [Chemical Abstracts, Vol. 53, p. 7161c(1959)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was6'-methoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p.170°-172° C. The yield of pure product was 41% of the theoretical value.

Anal. Calcd. for C₁₂ H₁₂ N₂ O₃ S: C, 54.53; H, 4.58; N, 10.61. Found: C,54.64; H, 4.67; N, 10.66.

EXAMPLE IX

The procedure described in Example II was repeated except that6-chlorothiochroman-4-one [Chemical Abstracts, Vol. 55, p. 12397c(1961)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was6'-chloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione,m.p.244°-246° C. The yield of pure product was 53% of the theoreticalvalue.

Anal. Calcd. for C₁₁ H₉ C1N₂ O₂ S: C, 49.16; H, 3.38; N, 10.43. Found:C, 49.23; H, 3.40; N, 10.39.

EXAMPLE X

The procedure described in Example II was repeated except that6-bromothiochroman-4-one [Arndt, Chemische Berichte, Vol. 58, p, 1612(1925)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was6-bromo-spiro-[imidazolidine-4,4'-thiochroman]2,5-dione, m.p. 234°-236°C. The yield of pure product was 56% of the theoretical value.

Anal. Calcd. for C₁₁ H₉ BrN₂ O₂ S: C, 42.18; H, 2.90; N, 8.95.

Found: C, 41.98; H, 2.92; N, 8.95.

EXAMPLE XI

The procedure described in Example II was repeated except that6,7-dichlorothiochroman-4-one (prepared as described in Preparation B)was the starting material employed in place of 6-methoxy-1-indanone,using the same molar proportions as before. In this particular case, thecorresponding final product obtained was6',7'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p.298°-300° C. The yield of pure product was 49% of the theoretical value.

Anal. Calcd. for C₁₁ H₈ Cl₂ N₂ O₂ S: C, 43.58; H, 2.66; N, 9.24. Found:C, 43.77; H, 2.85; N, 9.38.

EXAMPLE XII

The procedure described in Example II was repeated except that6-fluorothiochroman-4-one [Chemical Abstracts, Vol. 70, p. 47335x(1969)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p.200°-202° C. The yield of pure product was 60% of the theoretical value.

Anal. Calcd. for C₁₁ H₉ FN₂ O₂ S: C, 52.37; H, 3.60; N, 11.11. Found: C,52.36; H, 3.73; N, 11.05.

EXAMPLE XIII

The procedure described in Example II was repeated except that8-chlorothiochroman-4-one[Chemical Abstracts, Vol. 53, p. 7161c (1959)]was the starting material employed in place of 6-methoxy-1-indanone,using the same molar proportions as before. In this particular case, thecorresponding final product obtained was8'-chloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p.265°-267° C. The yield of pure product was 66% of the theoretical value.

Anal. Calcd. for C₁₁ H₉ ClN₂ O₂ S: C, 49.16; H, 3.38; N, 10.43. Found:C, 49.32; H, 3.50; N, 10.38.

EXAMPLE XIV

The procedure described in Example II was repeated except that7-chlorothiochroman-4-one [Chemical Abstracts, ]Vol. 52, p. 11044b(1958)] was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was7'-chloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, m.p.235°-237° C. The yield of pure product was 67% of the theoretical value.

Anal. Calcd. for C₁₁ H₉ ClN₂ O₃ S: C, 49.16; H, 3.38; N, 10.43. Found:C, 49.32; H, 3.36; N, 10.03.

EXAMPLE XV

The procedure described in Example II was repeated except that 7,8-dihydroquinolin-5(6H)-one (available from the Aldrich Chemical Company,Inc., Milwaukee, Wisconsin) was the starting material employed in placeof 6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was7',8'-dihydro-spiro[imidazolidine-4,5' (6H)-quinoline]-2,5-dione, m.p.275°-277° C. The yield of pure product was 39% of the theoretical value.

Anal. Calcd. for C₁₁ H₁₁ N₃ O₂ : C, 60.82; H, 5.10; N, 19.35. Found: C,60.41; H, 5.28; N, 19.29.

EXAMPLE XVI

The procedure described in Example II was repeated except that7-methoxy-1-tetralone (available from the Aldrich Chemical Company,Inc., Milwaukee, Wisconsin) was the starting material employed in placeof 6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was3',4'-dihydro-7'-methoxy-spiro-[imidazolidine-4,1'(2'H)naphthalene]-2,5-dione,m.p. 227°-229° C. The yield of pure product was 59% of the theoreticalvalue.

Anal. Calcd. for C₁₃ H₁₄ N₂ O₃ : C, 63.40; H, 5.73; N, 11.38. Found: C,63.19; H, 5.68; N, 11.30.

EXAMPLE XVII

The procedure described in Example II was repeated except that6,7-dimethoxytetralone [Howell and Taylor, Journal of the ChemicalSociety, p. 1248 (1958)]was the starting material employed in place of6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was3',4'-dihydro-6',7'-dimethoxy-spiro-[imidazolidine-4,1'(2H)naphthalene]-2,5-dione,m.p. 238°-240° C. The yield of pure product was 49% of the theoreticalvalue.

Anal. Calcd. for C₁₄ H₁₆ N₂ O₄ : C, 60.86; H, 5.84; N, 10.14. Found: C,60.94; H, 6.04; N, 10.48.

EXAMPLE XVIII

The procedure described in Example II was repeated except that6-methoxy-1-tetralone (available from the Aldrich Chemical Company,Inc., Milwaukee, Wisconsin) was the starting material employed in placeof 6-methoxy-1-indanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was3',4'-dihydro-6'-methoxy-spiro-[imidazolidine-4,1'(2'H)naphthalene]-2,5-dione,m.p. 219°-221° C. (literature m.p. 219°-220° C., according to U.S. Pat.No. 3,532,744)

EXAMPLE XIX

A solution of 1.18 g (0.005 mole) of6'-methoxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione (prepared asdescribed in Example II) in 10 ml. of methylene chloride was cooled to=65° C. and there was subsequently added thereto, in a dropwise manner,a solution consisting of 1.44 ml. (0.015 mole) of boron tribromidedissolved in 10 ml. of methylene chloride, while stirring the entirereaction mixture under a nitrogen atmosphere. The resulting mixture wasthen allowed to attain room temperature (˜25° C.) via removal of thecooling bath and thereafter kept at that point for a period of sevenhours. Upon completing this step, 30 ml. of water were added to themixture in a dropwise manner and the separated organic layer wassubsequently collected and dried over anhydrous magnesium sulfate. Afterremoval of the organic solvent (i.e., methylene chloride) by means ofevaporation under reduced pressure, there was ultimately obtained aresidual material that was subsequently recrystallized from ethanol togive 240 mg. (22%) of pure6'-hydroxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione, m.p. 253°-255° C.

Anal. Calcd. for C₁₁ H₁₀ N₂ O₃ : C, 60.54; H, 4.62; N, 12.84. Found: c,60.29, H, 4.66; N, 12.93.

EXAMPLE XX

A mixture consisting of 5.0 g. (0.033 mole) of 4-chromanone (availablefrom the Aldrich Chemical Company, Inc., Milwaukee, Wisconsin), 2.8 g.(0.043 mole) of potassium cyanide and 8.26 g. (0.086 mole) of powderedammonium carbonate in 40 ml. of ethanol was placed in a stainless-steelbomb and heated to 60° C. in an oil bath for a period of 24 hours. Thereaction mixture was then diluted with 300 ml. of water, boiled for 15minutes and after finally being cooled to room temperature, acidifiedwith 6N hydrochloric acid. The precipitated product so obtained was thencollected by means of suction filtration and subsequently recrystallizedfrom ethanol to give 2.5 g. (35%) of purespiro-[chroman-4,4'-imidazolidine]-2',5'-dione, m.p. 236°-238° C.(literature m.p. 236°-242° C., according to West German AuslegeschriftNo. 1,135,915).

Anal. Calcl. for C₁₁ H₁₁ NO₃ : C, 64.38; H, 5.40; N, 6.83. Found: C,64.18; H, 5.38; N, 6.83.

EXAMPLE XXI

The procedure described in Example XX was repeated except that6-methoxy-4-chromanone (British Pat. No. 1,024,645) was the startingmaterial employed in place of 4-chromanone, using the same molarproportions as before. In this particular case, the corresponding finalproduct obtained was6-methoxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, m.p. 170°-172°C. The yield of pure product was 32% of the theoretical value.

Anal. Calcd. for C₁₂ H₁₂ N₂ O₄ : C, 58.06; H, 4.87; N, 11.29. Found C,58.04, H, 4.98, N, 11.17.

EXAMPLE XXII

The procedure described in Example XX ws repeated except that6-fluoro-4-chromanone (prepared as described in Preparation A) was thestarting material employed in place of 4-chromanone, using the samemolar proportions as before. In this particular case, the correspondingfinal product obtained was6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, m.p. 239°-241°C. The yield of pure product was 36% of the theoretical value.

Anal. Calcd. for C₁₁ H₉ FN₂ O₃ : C, 55.93; H, 3.84; N, 11.86. Found: C,55.54; H, 3.88; N, 12.12.

EXAMPLE XXIII

the procedure described in Example XX was repeated except that6,7-dichloro-4-chromanone (West German Offenlegungschrift No. 1,928,127)was the starting material employed in place of 4-chromanone, using thesame molar proportions as before. In this particular case, thecorresponding final product obtained was6,7-dichloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, m.p.263°-265° C. The yield of pure product was 8% of the theoretical value.

Anal. Calcd. for C₁₁ H₈ Cl₂ N₂ O₃ : C, 46.02; H, 2.81; N, 9.76. Found:C, 45.83; H, 2.94; N, 9.65.

EXAMPLE XXIV

The procedure described in Example XX was repeated except that6,8-dichloro-4-chromanone [Huckle et al., Journal of MedicinalChemistry, Vol. 12, p. 277 (1969)]was the starting material employed inplace of 4-chromanone, using the same molar proportions as before. Inthis particulAR case, the corresponding final product obtained was6,8-dichloro-spiro-]chroman-4,4'-imidazolidine]-2',5'-dione, m.p.234°-235° C. The yield of pure product was 20% of the theoretical value.

Anal. Calcd. for C₁₁ H₈ Cl₂ N₂ O₃ : C, 46.02; H, 2.81; N, 9.76. Found:C, 45.81; H, 2.74; N, 9.69.

EXAMPLE XXV

A mixture consisting of 4.57 g. (0.025 mole) of 6-chloro-4-chromanone(available from the Aldrich Chemical Company, Inc., Milwaukee,Wisconsin), 2.8 g. (0.043 mole) of potassium cyanide and 9.6 g. (0.1mole) of powdered ammonium carbonate in 62.5 ml. of 50% aqueous ethanolwas heated to 60° C. for a period 48 hours. The reaction mixture wasthen cooled to room temperature (˜25° C.), diluted with 300 ml. of waterand thereafter acidified with 6N hydrochloric acid. The precipitatedsolids so obtained were subsequently collected by means of suctionfiltration and thereafter recrystallized from ethanol to yield 5.1 g.(81% ) of pure 6-chloro-spiro-[chroman-4,4°-imidazolidine]-2',5'-dione,m.p.. 268°-270° C. (literature m.p. 267°-270° C., according to WestGerman Auslegeschrift No. 1,135,915).

Anal. Calcd. for C₁₁ H₉ ClN₂ O₃ : C, 52.29; H, 3.59; N, 11.09. Found: C,52.15; H, 3.73; N, 10.99.

EXAMPLE XXVI

The procedure described in Example XXV was repeated except that5-methoxy-1-tetralone (available from the Aldrich Chemical Company,Inc., Milwaukee, Wisconsin) was the starting material employed in placeof 6-chloro-4-chromanone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was3',4'-dihydro-5'-methoxy-spiro-[imidazolidine-4,1'-(2'H)-naphthalene]-2,5-dione,m.p. 243°-243.5° C. (literature m.p. 242°-242.5° C., according to Sargeset al., Journal of Medicinal Chemistry, Vol. 16, p. 1003 (1937)].

Anal. Calcd. for C₁₃ H₁₄ N₂ O₃ : C, 63.40; H, 5.73; N, 11.38. Found: C,63.10; H, 5.70; N, 11.47.

EXAMPLE XXVII

The procedure described in Example XXV was repeated except that8-chloro-4-chromanone [Chemical Abstracts, Vol. 34, p. 4735⁸ (1940)] wasthe starting material employed in place of 6-chloro-4-chromanone, usingthe same molar proportions as before. In this particular case, thecorresponding final product obtained was8-chloro-spiro-[chroman-4,4'-inidazolidine]-2',5'-dione, m.p. 231°-233°C. (literature m.p. 231°-235° C., according to West GermanAuslegeschrift No. 1,135,915). The yield of pure product was 34% of thetheoretical value.

Anal. Calcd. for C₁₁ H₉ ClN₂ O₃ : C, 52.29; H, 3.59; N, 11.09. Found: C,52.21; H, 3.74; N, 11.12.

EXAMPLE XXVIII

The procedure described in Example XXV was repeated except that6-bromo-4-chromanone [Gilman et at., Journal of the American ChemicalSociety, Vol. 73, p. 4205 (1951)] was the starting material employed inplace of 6-chloro-4-chromanone, using the same molar proportions asbefore and the reaction temperature was 55° C. instead of 60° C. In thisparticular case, the corresponding final pr oduct obtained was6-bromo-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, m.p. 266°-268°C. (literature m.p. 264°-269° C., according to West GermanAuslegeschrfit No. 1,135,915). The yield of pure product was 15% of thetheoretical value.

EXAMPLE XXIX

To a solution of 1.09 g. (0.005 mole) ofspiro-[chroman-4,4'-imidazolidine]-2',5'-dione (prepared as described inExample XX) and 10 mg. of ferric chloride in 6 ml. of drydimethylformamide cooled to -40° C., there was added in a dropwisemanner and with constant agitation a solution consisting of 355 mg. ofchlorine gas dissovled in 4 ml. of dry dimethylformamide. The resultingreaction mixture was then maintained at -40° C. for a period of 30minutes (with stirring) before being allowed to attain roomtemperature(˜25° C.). After being kept at the latter point for a periodof 2.5 hours, it was poured into 250 ml. of ice-cold water to afford acrystalline precipitate that was subsequently collected by means ofsuction filtration and then air-dried to constant weight.Recrystallization of the latter material from glacial acetic acid (6ml.) then gave 0.31 g. (25%) of pure6-chloro-spiro-[chroman-4,4'-imidazolidine]- 2',5'-dione that wasidentical in every respect with the product of Example XXV.

EXAMPLE XXX

A mixture consisting of 252 mg. (0.001 mole) of6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione (prepared asdescribed in Example XII) in 10 ml. of methylene chloride, together with50 mg. of a 40% aqueous solution of tetrabutylammonium hydroxide and 224mg. (0.01 mole) of sodium periodate in 5 ml. of water was stirred atroom temperature (˜25° C.) for a period of one hour. The precipitatedsolids so obtained were subsequently collected by means of suctionfiltration and thereafter recrystallized from ethanol (3 ml.) to yield60 mg. (22%) of pure6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide,m.p. 289°-291° C.

Anal. Calcd. for C₁₁ H₉ FN₂ O₃ S: C, 49.25; H, 3.38; N, 10.44.

Found: C, 49.27; H, 3.35; N, 10.35.

EXAMPLE XXXI

To a suspension of 0.595 g. (0.00236 mole) of6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione (prepared asdescribed in Example XII) in 50 ml. of chloroform contained in a 250 ml.three-necked round-bottomed reaction flask, there was added in smallportions over a one-hour period 1.00 g. (0.00579 mole) ofm-chloroperoxybenzoic acid. The resulting slurry was then stirred atroom temperature (˜25° C.) for a period of 36 hours and finally dilutedwith 500 ml. of ethyl acetate. The yellow organic layer so obtained wasnext washed with four-50 ml. portions of saturated aqueous sodiumbicarbonate solution, dried over anhydrous magnesium sulfate, filteredand the solvent portion then removed in vacuo to afford 0.50 g. (74.5%)of crude6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxidein the form of a white crystalline residue. Recrystallization fromethanol/ethyl acetate/n-hexane then gave the pure material (m.p.179°-180° C. with decomp.) as a first crop of fine white crystals(yield, 0.295 g.). Two additional recrystallizations from ethanol/ethylacetate raised the melting point of the analytical sample to 184°-186°C. (decomp.).

Anal. Calcd. for C₁₁ H₉ FN₂ O₄ S.O.5CH₃ COOC₂ H₅ ; C, 47.55; H, 3.99; N,8.53.

C, 47.54; H, 3.93; N, 8.56.

EXAMPLE XXXII

The procedure described in Example XXXI was repeated except that 0.234g. (0.001 mole) of spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione(prepared as described in Example VII) and 0.426 g. (0.00247 mole) ofm-chloro-peroxybenzoic acid were reacted together to afford 0.20 g.(75%) of purespiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide.Recrystallization from methanol/ethanol/n-hexane then gave theanalytical sample (m.p. 280°-281° C.).

Anal. Calcd. for C₁₁ H₁₀ N₂ O₄ S: C, 49.61; H, 3.78; N, 10.52.

Found C, 49.82; H, 3.85; N, 10.19.

EXAMPLE XXXIII

A mixture consisting of 1.0 g. (0.00549 mole) ofthioindane-3-one,1,1-dioxide [Regitz, Chemische Berichte, Vol. 98, p. 36(1965)], 0.613 g. (0.0094 mole) of potassium cyanide and 21.9 g. (0.021mole) of ammonium carbonate in 14 ml. of 50% aqueous ethanol was placedin a 50 ml. round-bottomed reaction flask and heated at 60° C. for aperiod of 48 hours while under a nitrogen atmosphere. The reactionmixture was then diluted with 70 ml. of water, a trace of solid wasremoved by means of filtration and the filtrate was subsequentlyacidified with 6 N hydrochloric acid. The precipitated product obtainedin this manner was thereafter recovered by filtration, redissolved in 4N aqueous potassium hydroxide and finally reacidified with 6 Nhydrochloric acid. The acidified solution containing the product wassaturated with sodium chloride and then extracted with six-150 ml.portions of fresh ethyl acetate, with the resulting organic layerssubsequently being combined and dried over anhydrous magnesium sulfate.Upon removal of the drying agent by means of filtration and the organicsolvent by means of evaporation under reduced pressure, there wasobtained 0.50 g. (36%) of purespiro-[imidazolidine-4,3'-thioindan]-2,5-dione-1,1'-dioxide, m.p. 287°C. (decomp.) after two recrystallizations from ethanol/ethylacetate/n-hexane.

Anal. Calcd. for C₁₀ H₈ N₂ O₄ S: C, 47.61; H, 3.20; N, 11.11 Found: C,47.77; H, 3.28; N, 10.85.

EXAMPLE XXXIV

A mixture consisting of 2.75 g. (0.01562 mole) of6,8-dimethyl-4-chromanone [Chemical Abstracts, Vol. 58, p. 13900c(1964)], 3.5 g. (0.0538 mole) of potassium cyanide and 10.5 g. (0.109mole) of ammonium carbonate in 60 ml. of 50% aqueous ethanol was placedin a 125 ml. round-bottomed reaction flask and heated via an oil bath at65° C. for a period of 48 hours while under a nitrogen atmosphere. Thereaction mixture was then cooled to room temperature (˜25° C.) andfiltered and the resulting filtrate subsequently extracted with 50 ml.of diethyl ether. The resulting aqueous layer was then saved andsubsequently acidified to pH 2.0 with 3 N hydrochloric acid (cooling wasnecessary). The cloudy mixture so obtained was next extracted withthree-200 ml. portions of ethyl acetate and the combined organic layerswere thereafter re-extracted with three-50 ml. portions of 4 N aqueouspotassium hydroxide. The combined basic aqueous layers were reacidifiedagain to pH 2.0 with 3 N hydrochloric acid in the same manner as beforeand then saturated with sodium chloride prior to extraction withthree-200 ml. portions of fresh ethyl acetate. The combined organiclayers were subsequently dried over an anhydrous magnesium sulfate andfiltered. Upon removal of the solvent from the filtrate by means ofevaporation under reduced pressure, there was ultimately obtained 2.50g. (65%) of 6,8-dimethyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione,m.p. 185°-190° C. (decomp.). Two recrystallizations from aqueous ethanolthen gave analytically pure material (m.p. 188°-189° C.).

Anal. Calcd. for C₁₃ H₁₄ N₂ O₃ : C, 63.40; H, 5.73; N, 11.38. Found: C,63.05; H, 5.69; N, 11.33.

EXAMPLE XXXV

The following spiro-hydantoin compounds are prepared by employing theprocedures described in the previous examples, starting from readilyavailable materials in each instance:

6'-chloro-spiro-[imidazolidine-4,1'-indan]-2,5-dione

6'-bromo-spiro-[imidazolidine-4,1'-indan]-2,5-dione

5'-fluoro-spiro-[imidazolidine-4,1'-indan]-2,5-dione

5'-methyl-spiro-[imidazolidine-4',1-indan]-2,5-dione

6'-(n-butyl)-spiro-[imidazolidine-4',1-indan]-2,5-dione

5'-hydroxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione

6'-ethoxy-spiro-[imidazoline-4,1'-indan]-2,5-dione

5'-(n-butoxy)-spiro-[imidazolidine-4,1'-indan]-2,5-dione

5',6'-dichloro-spiro-[imidazolidine-4,1'-indan]-2,5-dione

5',6'-dimethyl-spiro-[imidazolidine-4',1-indan]-2,5-dione

5',6'-di(n-propyl)-spiro-[imidazolidine-4',1-indan]-2,5-dione

5',6'-di(n-propoxy)-spiro-[imidazolidine-4,1'-indan]-2,5-dione

5',6'-ethylenedioxy-spiro-[imidazolidine-4,1'-indan]-2,5-dione

8-bromo-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6-(n-butyl)-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

7-methyl-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6-hydroxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6-ethoxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6-(n-butoxy)-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

7-isopropoxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6,8-di(n-butyl)-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6,7-dimethoxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

6,8-di(n-butoxy)-spiro-[chroman-4,4'-imidazoline]-2',5'-dione

6,7-ethylenedioxy-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione

8'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

7'-bromo-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6'-hydroxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6'-methyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

7'-(n-butyl)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

7'-(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6'-isopropoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',8'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',7'-dimethyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',8'-di(n-butyl)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',7'-dimethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',7'-diethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',8'-di(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',7'-methylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

6',7'-ethylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione

spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

8'-chloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6'-bromo-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6'-methyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

7'-(n-butyl)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6'-methoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

7'-(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-dimethyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',8'-di(n-butyl)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-dimethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-diethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',8'-di(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-methylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

6',7'-ethylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1'-oxide

8'-chloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6'-methyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

7'-(n-butyl)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6'-methoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

7'-(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-dimethyl-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-dimethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-diethoxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',8'-di(n-butoxy)-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-methylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

6',7'-ethylenedioxy-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione-1',1'-dioxide

spiro-[imidazolidine-4,4'-isothiochroman]-2,5-dione-1',1'-dioxide

3',4'-dihydro-7'-fluoro-spiro-[imidazolidine-4,1'-(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-7'-chloro-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6'-bromo-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-5'-isopropyl-spiro-[imidazolidine-4,1'-(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6'-methyl-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-7'-(n-butyl)-spiro[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-5'-hydroxy-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-5'-ethoxy-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-7'-(n-butoxy)-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6',7'-dichloro-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6',7'-diethyl-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6',7'-dimethoxy-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6,7-di(n-propoxy)-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6',7'-methylenedioxy-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

3',4'-dihydro-6',7'-ethylenedioxy-spiro-[imidazolidine-4,1'(2'H)-naphthalene]-2,5-dione

6',7'-dihydro-spiro-[imidazolidine-4,5'(5H)-pyridine]-2,5-dione

EXAMPLE XXXVI

The sodium salt of6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione is prepared bydissolving said compound in water containing an equivalent amount inmoles of sodium hydroxide and then freeze-drying the mixture. In thisway, the desired alkali metal salt of the hydantoin is obtained in theform of an amorphous powder which is freely soluble in water.

In like manner, the potassium and lithium salts are also similarlyprepared, as are the alkali metal salts of all the other spiro-hydantoincompounds of this invention which are reported in Examples I-XXI andXXIII-XXXV, respectively.

EXAMPLE XXXVII

The calcium salt of6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione is prepared bydissolving said compound in water containing an equivalent amount inmoles of calcium hydroxide and then freeze-drying the mixture. Thecorresponding magnesium salt is also prepared in this manner, as are allthe other alkaline-earth metal salts not only of this particularcompound, but also of those spiro-hydrantoins previously described inExamples I-XXI and XXIII-XXXV, respectively.

EXAMPLE XXXVIII

A dry solid pharmaceutical composition is prepared by blending thefollowing materials together in the proportions by weight specifiedbelow:

    ______________________________________                                        6-Fluoro-spiro-[chroman-4,4'-imidazolidine]-                                  2',5'-dione                 50                                                Sodium citrate              25                                                Alginic acid                10                                                Polyvinylpyrrolidone        10                                                Magnesium stearate           5                                                ______________________________________                                    

After the dried composition is thoroughly blended, tablets are punchedfrom the resulting mixture, each tablet being of such size that itcontains 200 mg. of the active ingredient. Other tablets are alsoprepared in a similar fashion containing 25, 50 and 100 mg. of theactive ingredient, respectively, by merely using the appropriate amountof the hydantoin compound in each case.

EXAMPLE XXXIX

A dry solid pharmaceutical composition is prepared by combining thefollowng materials together in the proportions by weight indicated:

    ______________________________________                                        6-Chloro-spiro-[chroman-4,4'-imidazolidine]-                                  2',5'-dione                 50                                                Calcium carbonate           20                                                Polyethylene glycol, average molecular                                        weight 4000                 30                                                ______________________________________                                    

The dried solid mixture so prepared is then thoroughly agitated so as toobtain a powdered product that is completely uniform in every respect.Soft elastic and hard-filled gelatin capsules containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each instance so as to provide each capsule with250 mg. of the active ingredient.

EXAMPLE XL

The following spiro-hydantoin compounds of Preparation C and ExamplesI-XXVIII and XXX-XXXIV, respectively, were tested for their ability toreduce or inhibit aldose reductase enzyme activity via the procedure ofS. Hayman et al., as described in the Journal of Biological Chemistry,Vol. 240, p. 877 (1965) and as modified by K. Sestanj et al. in U.S.Pat. No. 3,821,383. In every case, the substrate employed was partiallypurified aldose reductase enzyme obtained from calf lens. The resultsobtained with each compound are expressed below in terms of percentinhibition of enzyme activity with respect to the various concentrationlevels tested:

    ______________________________________                                                   Percent Inhibition (%)                                             Compound     10.sup.-4 M                                                                            10.sup.-5 M                                                                            10.sup.-6 M                                                                          10.sup.-7 M                             ______________________________________                                        Prod. of Prep. C                                                                           72       34       13     7                                       Prod. of Ex. I                                                                             73       39       18     -11                                     Prod. of Ex. II                                                                            97       61       17     1                                       Prod. of Ex. III                                                                           74       12       22     -1                                      Prod. of Ex. IV                                                                            90       81       35     9                                       Prod. of Ex. V                                                                             92       67       25     3                                       Prod. of Ex. VI                                                                            82       60       13     -10                                     Prod. of Ex. VII                                                                           92       64       10     -5                                      Prod. of Ex. VIII                                                                          76       60       18     7                                       Prod. of Ex. IX                                                                            79       87       71     30                                      Prod. of Ex. X                                                                             32       --       --     --                                      Prod. of Ex. XI                                                                            67       84       76     69                                      Prod. of Ex. XII                                                                           81       77       66     38                                      Prod. of Ex. XIII                                                                          60       --       --     --                                      Prod. of Ex. XIV                                                                           70       --       --     --                                      Prod. of Ex. XV                                                                            83       54       9      -2                                      Prod. of Ex. XVI                                                                           54       --       23     --                                      Prod. of Ex. XVII                                                                          82       26       8      16                                      Prod. of Ex. XVIII                                                                         72       38       15     7                                       Prod. of Ex. XIX                                                                           93       31       11     -30                                     Prod. of Ex. XX                                                                            73       64       -9     -16                                     Prod. of Ex. XXI                                                                           100      92       35     7                                       Prod. of Ex. XXII                                                                          84       58       52     3                                       Prod. of Ex. XXIII                                                                         59       96       91     84                                      Prod. of Ex. XXIV                                                                          85       90       78     81                                      Prod. of Ex. XXV                                                                           73       81       77     64                                      Prod. of Ex. XXVI                                                                          72       49       5      0                                       Prod. of Ex. XXVII                                                                         87       85       52     6                                       Prod. of Ex. XXVIII                                                                        74       --       --     --                                      Prod. of Ex. XXX                                                                           87       80       64     16                                      Prod. of Ex. XXXI                                                                          85       74       74     28                                      Prod. of Ex. XXXII                                                                         94       69       31     2                                       Prod. of Ex. XXXIII                                                                        81       64       22     4                                       Prod. of Ex. XXXIV                                                                         71       84       54     17                                      ______________________________________                                    

EXAMPLE XLI

The following spiro-hydantoin compounds of Preparation C and ExamplsI-IV, VII-IX, XI-XVII, XIX-XXV, XXVII and XXX-XXXIII, respectively, weretested for their ability to reduce or inhibit sorbitol accumulation inthe sciatic nerve of streptozotocinized (i.e., diabetic) rats by theprocedure essentially described in U.S. Pat. No. 3,821,383. In thepresent study, the amount of sorbitol accumulation in the sciatic nerveswas measured 27 hours after induction of diabetes. The compounds wereadministered orally at the dose levels indicated at 4, 8 and 24 hoursfollowing the administration of streptozotocin. The results obtained inthis manner are presented below in terms of percent inhibition (%)afforded by the test compound as compared to the case where no compoundwas administered (i.e., the untreated animal where sorbitol levelsnormally rise from approximately 50-100 mM/g. tissue to as high as 400mM/g. tissue in the 27-hour test period):

    ______________________________________                                                   Percent Inhibition (%)                                             Compound      0.75    1.5    2.5  5.0  10 mg./kg.                             ______________________________________                                        Prod. of Prep C                                                                             --      --     --    3   40                                     Prod. of Ex. I                                                                              --      29     --   52   67                                     Prod. of Ex. II                                                                             --      --     --    6   54                                     Prod. of Ex. III                                                                            --      --     --   45   --                                     Prod. of Ex. IV                                                                             --      --     --   33   49                                     Prod. of Ex. V                                                                              --      --     --    9   --                                     Prod. of Ex. VII                                                                            --      --     --   39   65                                     Prod. of Ex. VIII                                                                           --      --     --   26   --                                     Prod. of Ex. IX                                                                             --      --     58   --   --                                     Prod. of Ex. XI                                                                             --      --     --   59   --                                     Prod. of Ex. XII                                                                            13      45     74   --   --                                     Prod. of Ex. XIII                                                                           --      5      --   --   --                                     Prod. of Ex. XIV                                                                            --      26     --   --   --                                     Prod. of Ex. XV                                                                             --      --     --    5   52                                     Prod. of Ex. XVI                                                                            --      --     --   25   44                                     Prod. of Ex. XVII     --     --   --   3                                      Prod. of Ex. XIX                                                                            --      --     --   --   15                                     Prod. of Ex. XX                                                                             --      --     34   58   77                                     Prod. of Ex. XXI                                                                            --      --     24   --   --                                     Prod. of Ex. XXII                                                                           45      72     --   --   --                                     Prod. of Ex. XXIII                                                                          --      64     --   --   --                                     Prod. of Ex. XXIV                                                                           82      --     --   --   --                                     Prod. of Ex. XXV                                                                            64      84     --   --   --                                     Prod. of Ex. XXVII                                                                          --      30     --   --   --                                     Prod. of Ex. XXX                                                                            --      35     --   --   --                                     Prod. of Ex. XXXI                                                                           --      --     47   68   --                                     Prod. of Ex. XXXII                                                                          28      --     12   --   --                                     Prod. of Ex. XXXIII                                                                         --      --     --    5   --                                     ______________________________________                                    

EXAMPLE XLII

6-Fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione (the product ofExample XXII) was tested for its ability to reverse already-elevatedsorbitol levels in streptozotocin-induced diabetic rats of two weeksduration (i.e., chronic) by administering said compound orally to theanimals for a period of seven days. In this study, the sorbitoldeterminations were carried out in both the sciatic nerve and the lens.Streptozotocin was first administered to the animals at 65 mg./kg., viathe intravenous route. The animals then remained untreated for a periodof two weeks. At the end of this time, a "control" group of eight rats(Control Group I) was sacrificed for baseline sorbitol determinations,while the remaining two groups of seven animals each either received6-fluoro-spiro[-chromam-4,4'-imidazolidine]-2',5'-dione at 2.5 mg./kg.,twice a day, or simply water alone (Control Group II). After seven days,the rats were sacrificed (three hours post dose) and it was found thatwhile sciatic nerve sorbitol levels in the control group (Control GroupII) had risen slightly above baseline values and lens sorbitol valueshad stabilized with respect to same, substantial rreductions in sorbitollevels had occurred in both the sciatic nerve (68%) and lens (71%) ofthe treated group (i.e., those animals receiving the aforesaid testcompound).

EXAMPLE XLIII

The ability of 6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dioneto prevent or inhibit galactitol formation in acutely galactosemic ratswas determined by administering said compound to the animals, via theirfeed, for a period of seven days. In this study, normal male rats werefirst divided into groups of six animals each and then fed a 30%galactose diet together with the compound to be administered at threedifferent dosage levels. One group of animals received6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione at 10 mg./kg.and another at 20 mg./kg., respectively. A control group of nine animalsreceived a 30% galactose diet without any compound. At the end of theseven-day period, lenses were removed for galactitol determination andit was found that while polyol levels in the control group had risenfrom essentially undetectable amounts to a value of well over 30μmoles/g., in those rats receiving the test compound in the diet inaddition to galactose, there was definitely a very pronounced inhibitionof galactitol values at the two higher dose levels tested (e.g., 72% at20 mg./kg. and 40% at 10 mg./kg., respectively).

EXAMPLE XLIV

To determine the effect of6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione on cataractformation in galactosemia, rats were fed a 30% galactose diet with andwithout this compound for a period of 29 days and eye examinations alsowere routinely conducted approximately twice a week throughout thisperiod. The experimental animals received the test compound mixed in thefood at concentration levels necessary to afford approximate doses of 10mg./kg. and 20 mg./kg., respectively. Control animals received thegalactose diet alone (i.e., without the compound). After 8-14 days, itwas found that lenticular opacities had developed in 90% of the eyes ofthe control animals as compared to no opacities being present in thecases of those rats receiving6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione at either 10mg./kg. or 20 mg./kg., as aforesaid. At the end of 17 days, it was foundthat opacities were present in 100% of the eyes of the control animals,while only 6% of the eyes of those rats receiving6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione at 10 mg./kg.were actually affected. The corrsponding value obtained in ratsreceiving the test compound at 20 mg./kg. was 0%. This delay in cataractformation continued in all the treated groups until the 22-day mark, atwhich point lenticular opacities were observed in greater than 90% ofthe eyes of those animals receiving the test compound at the 10 mg./kg.dose level. However, in rats receiving6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione at 20 mg./kg.,an impressive delay in cataract formation wa still observed at the29-day mark, as evidenced by the fact that only 37% of the eyes of theanimals in the treated group showed lenticular opacities.

EXAMPLE XLV

The effectiveness of6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione in delayingcataract development in rats is further highlighted by the testprocedure of Example XLIV by giving careful consideration to theseverity of the lenticular opacities involved. In this study, thepercentage of lens areas involed were monitored throughout the 29-dayperiod and the results obtained served as an index of severity. In thisway, it was found that after 17 days, 75% of the control lenses involvedshowed an area of involvement which was never less than 10%. On theother hand, corresponding values of 6% and 0% were respectively obtainedin the case of those rats receiving6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione at 10 mg./kg.and 20 mg./kg. dose levels. As a matter of fact, the severity oflenticular opacities in the treated groups was always less than thatfound in the control group, including the values obtained at the end ofthe 29-day mark.

EXAMPLE XLVI

The compounds prepared in Example XXXV are subjected to the testprocedure of Example XL and are active as aldose reductase inhibitors atdoses corresponding to at least one of the concentration levelspreviously indicated.

What is claimed is:
 1. A compound of the formula: ##STR10## or the basesalts thereof with pharmacologically acceptable cations, whereinX andX², when taken separately, are each lower alkoxy of 1-14 carbons, andwhen taken together are --OCH₂ (CH₂)_(n) O-- located at the5,6-positions of the molecule; and X is hydrogen when X³ is fluorine,chlorine or bromine; or X and X³, when taken separately, are eachchlorine and when taken together are --OCH₂ (CH₂)_(n) O-- located at the6,7-positions of the molecule; and n is zero or one.
 2. A compound ofthe formula: ##STR11## or the base salts thereof with pharmacologicallyacceptable cations, whereinX and X², when taken separately, are eachlower alkoxy of 1-4 carbons, and when taken together are --OCH₂(CH₂)_(n) O-- located at the 5,6-positions of the molecule; and n iszero or one.
 3. A compound of the formula ##STR12## or the base saltsthereof with pharmacologically acceptable cations, whereinX is hydrogenand X³ is fluorine, chlorine or bromine; or X and X³, when takenseparately, are each chlorine and when taken together are --OCH₂(CH₂)_(n) O-- located at the 6,7-positions of the molecule; and n iszero or one.